Magnetic Device for Sorting Biological Objects

ABSTRACT

A magnetic device for processing biological objects including a soft magnetic center pole having a bottom end and a tapered tip end; first and second soft magnetic side poles disposed on opposite sides of the soft magnetic center pole and respectively having first and second bottom ends, the first and second soft magnetic side poles respectively having first and second top ends that bend inward toward the soft magnetic center pole with a first outward side of the first top end and a second outward side of the second top end being substantially coplanar; a magnetic flux source generating magnetic flux in the soft magnetic center pole and the first and second soft magnetic side poles; and a channel plate having a channel embedded therein and a first planar surface that is operable to be in contact with or in close proximity to the first and second outward sides.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority to provisional application No.63/406,437, filed on Sep. 14, 2022, and is a continuation-in-part ofapplication Ser. No. 16/729,398, filed on Dec. 29, 2019, which is acontinuation-in-part of application Ser. No. 15/911,115, filed on Mar.3, 2018. All of these applications are incorporated herein by referencein their entirety, including their specifications.

BACKGROUND

The present invention relates to a device for sorting biologicalobjects, and more particularly, to embodiments of a magnetic device forsorting magnetic or magnetically labeled biological objects in a fluid.

The separation and sorting of biological objects or cells is critical tovarious biomedical applications, such as diagnostics and therapeutics.Biological cells may be sorted based on their respective physicalproperties, such as size and density, and biochemical properties, suchas surface antigen expression.

In magnetic force-based separation, a cell, which typically is notmagnetic, can be magnetized for magnetic sorting purpose by attachingantibody-conjugated magnetic beads thereto, a process also known asmagnetic labeling. FIG. 1A shows a cell 50 including a plurality ofsurface markers or antigens 52 on the cell surface thereof, and aplurality of antibody-conjugated magnetic beads 54 suspended in a fluid.Each of the antibody-conjugated magnetic beads 54 includes a magneticparticle 56 conjugated with one or more antibodies or other ligands 58,such as peptides and aptamers, that correspond to the surface markers52. After an incubation period, the magnetic beads 54 may be directlyattached to the cell 50 via the antigen-antibody interaction to form amagnetically labeled cell as shown in FIG. 1B, in a process known asdirect labeling.

Alternatively, magnetic beads may be attached to a cell through anindirect labeling process. FIG. 2A shows a cell 50 including a pluralityof surface markers or antigens 52 on the cell surface thereof, aplurality of intermediary links 60, and a plurality of magnetic beads 62suspended in a fluid. Each of the intermediary links 60 includes one ormore linking molecules 64, such as biotin or phycoerythrin (PE),conjugated to a primary antibody 66 that corresponds to the surfacemarkers 52 of the cell 50. Each of the magnetic beads 62 includes amagnetic particle 56 conjugated with one or more secondary antibodies orligands 68, such as streptavidin, that target the linking molecules 64.After an incubation period, the intermediary links 60 may attach to thecell 50 via the antigen-antibody interaction, and the magnetic beads 62may further attach to the intermediary links 60 via PE-antibody,biotin-streptavidin, or other types of interactions, thereby forming amagnetically labeled cell as shown in FIG. 2B.

After cells in sample fluid are magnetically labeled, they can be sortedor separated from the other non-labeled cells or biological objects inthe sample fluid by a magnetic separator device. FIG. 3A shows aconventional magnetic separator device 70 comprising a container vessel72 for holding the sample fluid 74 that contains the magneticallylabeled cells 76 and a permanent magnet 78 placed in close proximity toa wall of the container vessel 72. The permanent magnet 78 generates amagnetic field in the container vessel 72 with the magnetic fieldgradient pointing towards the permanent magnet 78. After sufficienttime, the magnetically labeled cells 76 will be gradually pulled by theforce produced by the magnetic field towards the vessel wall and form anaggregate at the vessel wall, as shown in FIG. 3B. Because the magneticfield strength rapidly decreases as the distance from the permanentmagnet 78 increases, the size of the vessel 72 and the sample fluidvolume will be adversely limited.

FIG. 4 illustrates another conventional magnetic separator device 80that separates magnetically labeled cells in a static fluid samplecontained in one or more wells 82. The magnetic device 80 uses multipleferromagnetic poles 84, each of which has a trapezoidal tip, toconcentrate the magnetic flux generated by multiple permanent magnets 86attached thereto to increase the magnetic field strength and gradientnear their tips. The corresponding magnetic field distribution, asdelineated by magnetic field lines 88, shows that the magnetic field isstrongest between the side surfaces of adjacent trapezoidal tips, asindicated by the small spacing between the field lines 88. By contrast,the magnetic field gradient is much weaker above the pole tips, asindicated by the large spacing between the field lines 88. Accordingly,this necessitates the bottom portion of each well 82 to be disposedbetween the side surfaces of the pole tips, where the magnetic field isstrong. The magnetically labeled cells in the conical-shaped wells 82will be collected or condensed in or near the bottom of the wells 82adjacent to the side surfaces of the trapezoidal tips of theferromagnetic poles 84. Compared with the magnetic separator device 70utilizing only the permanent magnet 78, the magnetic separator device 80can improve the magnetic field and gradient by using the ferromagneticpoles 84 to concentrate the magnetic flux. Both devices 80 and 90,however, are designed to treat static sample fluid and may thus havelimited throughput.

FIG. 5A illustrates a conventional magnetic separator device 90 thatseparates the magnetically labeled cells 76 as the sample fluid flowsthrough the device 90. The device 90 includes a conduit or column 92disposed between a pair of permanent magnets 94 that generate a magneticfield 96 across the column 92. The column 92 is filled with a porousaggregate of ferromagnetic or ferrimagnetic particles or spheres 98 thatare magnetized by the magnetic field 96 and produce relatively stronglocalized magnetic field and field gradient in small gaps between theparticles or spheres 98, thereby attracting the magnetically labeledcells 76 to the surface of the particles or spheres 98. Compared withthe magnetic beads attached to the magnetically labeled cells 76, theferromagnetic or ferrimagnetic particles or spheres 98 are much largerand may produce remanent magnetization after the permanent magnets 94are removed from the column 92. The remanent magnetization would preventor hinder the detachment of the magnetically labeled cells 76 from thesurface of the particles or spheres 98 after the separation process.While the magnetic separator device 90 may operate in a continuous flowmanner and thus may have a higher throughput than the magneticseparators 70 and 80 that operate in a static manner, the recovery ofthe magnetically labeled cells in certain applications (e.g., positiveselection process where the magnetically labeled cells are the targetcells) may be lower without vigorously flushing the column 92 todislodge the magnetically labeled cells 76 from the surface of theparticles or spheres 98.

The porous aggregate of soft magnetic particles or spheres 98 in thecolumn 92 may be replaced by one or more meshes 102 made of aferromagnetic or ferrimagnetic material as shown in FIG. 5B. Themagnetic separator device 100 may reduce the remanent magnetizationencountered in the device 90 because the wires in mesh 102 have smallerdimensions than the ferromagnetic or ferrimagnetic particles or spheres98. However, the larger opening between adjacent wires in the mesh 102may also weaken the localized magnetic field, thereby decreasing thedevice throughput. Both column-based devices 90 and 100 may introducedunwanted contaminants into the sample fluid as it flows through theferromagnetic or ferrimagnetic material in the column 92.

FIG. 6 shows another magnetic separator device 104, which operates in acontinuous flow manner without using a column that contains a porousaggregate of ferromagnetic or ferrimagnetic material, thereby obviatingthe potential contamination and recovery issues. The column-free device104 includes a conduit 106 surrounded by a radial array of ferromagneticpoles 108 that conduct magnetic flux from a plurality of permanentmagnets 110 and 112. The sample fluid flows through the conduit 106along a direction perpendicular to the figure. The magnetic separatordevice 104 essentially rearranges the linear array of the ferromagneticpoles 84 of the static magnetic separator device 80 in a radial mannerto create a magnetic periodic field in the center of the radiallyarranged ferromagnetic poles 108 and permanent magnets 110 and 112. Likethe static device 80 shown in FIG. 4 , the corresponding magnetic fielddistribution generated by the device 104, as delineated by magneticfield lines 114 between the trapezoidal tips of the ferromagnetic poles108, shows that the magnetic field is strongest between the sidesurfaces of adjacent trapezoidal tips, as indicated by the small spacingbetween the field lines 114, and much weaker above the pole tips (i.e.,inside the conduit 106), as indicated by the large spacing between thefield lines 114. However, unlike the wells 82 that extend into theregions between the side surfaces of two adjacent trapezoidal tips, theconduit 106 of the magnetic separator device 104 does not extend intosuch regions, thereby making the magnetic field in the conduit 106considerably weaker. This is further exacerbated by the limited timeexposed to the magnetic field as the sample fluid flows through theconduit 106.

For the foregoing reasons, there is a need for a magnetic separatordevice that can rapidly separate or sort magnetically labeled cellswithout introducing potential contaminants into the sample.

SUMMARY

The present invention is directed to a device that satisfies this need.A magnetic separator device having features of the present invention forsorting biological objects includes a soft magnetic center pole having abottom end and a tapered tip end; first and second soft magnetic sidepoles disposed on opposite sides of the soft magnetic center pole andrespectively having first and second bottom ends, the first and secondsoft magnetic side poles respectively having first and second top endsthat bend inward toward the soft magnetic center pole with a firstoutward side of the first top end and a second outward side of thesecond top end being substantially coplanar; a magnetic flux sourcegenerating magnetic flux in the soft magnetic center pole and the firstand second soft magnetic side poles; and a channel plate having achannel embedded therein and a first planar surface that is operable tobe in contact with or in close proximity to the first and second outwardsides. The magnetic separator device may further include a soft magnetictop shield operable to be in contact with or in close proximity to asecond planar surface of the channel plate.

According to another aspect of the present invention, a magneticseparator device having features of the present invention for sortingbiological objects includes a soft magnetic center pole having a bottomend and a tapered tip end; first and second soft magnetic side polesdisposed on opposite sides of the soft magnetic center pole andrespectively having first and second bottom ends, the first and secondsoft magnetic side poles respectively having first and second top endsthat are substantially coplanar; a channel plate including a channelembedded therein and a first planar surface operable to be in contactwith or in close proximity to the tapered tip end; a soft magnetic topshield operable to be in contact with or in close proximity to a secondplanar surface of the channel plate; and a magnetic flux sourcegenerating magnetic flux in the soft magnetic center pole, the first andsecond soft magnetic side poles, and the soft magnetic top shield.

According to still another aspect of the present invention, a magneticseparator device having features of the present invention for sortingbiological objects includes a soft magnetic center pole having a bottomend and a tapered tip end; first and second soft magnetic side polesdisposed on opposite sides of the soft magnetic center pole, the firstsoft magnetic side pole having a first bottom end and a first top end,the second soft magnetic side pole having a second bottom end and asecond top end, the first and second top ends bending inward toward thesoft magnetic center pole and each having a chisel edge profile with abevel side facing outward away from the soft magnetic center pole; amagnetic flux source generating magnetic flux in the soft magneticcenter pole and the first and second soft magnetic side poles; aflexible conduit nestled in a gap formed between the tapered tip end andthe bevel sides of the first and second top ends; and a soft magneticpress operable to push and deform the flexible conduit nestled in thegap.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other features, aspects, and advantages of the presentinvention will become better understood with regard to the followingdescription, appended claims, and accompanying drawings where:

FIGS. 1A and 1B illustrate formation of a magnetically labeled cell bydirect labeling process;

FIGS. 2A and 2B illustrate formation of a magnetically labeled cell byindirect labeling process;

FIGS. 3A and 3B illustrate sorting of magnetically labeled cells by aconventional static magnetic separator device;

FIG. 4 illustrates another conventional magnetic separator device forsorting magnetically labeled cells in a static sample fluid;

FIGS. 5A and 5B illustrate two conventional magnetic separator devicesthat utilize a column filled with ferromagnetic or ferrimagnetic objectsfor sorting magnetically labeled cells flowing through the columns;

FIG. 6 is a cross-sectional view corresponding to a magnetic separatordevice for sorting magnetically labeled cells flowing through a conduit;

FIG. 7 is a cross-sectional view showing an embodiment of the presentinvention as applied to a magnetic separator device for separating orisolating magnetically labeled biological objects;

FIG. 8 is a cross-sectional view illustrating the accumulation ofmagnetically labeled biological objects on the channel wall of thedevice of FIG. 7 during a sorting operation;

FIG. 9 is a cross-sectional view illustrating that the channel plate ispositioned in close proximity to rather than in contact with the firstand second outward sides of the device of FIG. 7 during a sortingoperation;

FIG. 10 is a cross-sectional view illustrating that the channel plate isremoved from the magnetic field generator of the device of FIG. 7 aftera sorting operation;

FIG. 11 is a cross-sectional view showing another embodiment of thepresent invention as applied to a magnetic separator device using twopermanent magnets for separating or isolating magnetically labeledbiological objects;

FIG. 12 is a cross-sectional view showing still another embodiment ofthe present invention as applied to a magnetic separator device usingthree permanent magnets for separating or isolating magnetically labeledbiological objects;

FIG. 13 is a cross-sectional view showing yet another embodiment of thepresent invention as applied to a magnetic separator device using threepermanent magnets for separating or isolating magnetically labeledbiological objects;

FIG. 14 is a cross-sectional view showing still yet another embodimentof the present invention as applied to a magnetic separator device forseparating or isolating magnetically labeled biological objects;

FIGS. 15-17 are cross-sectional views of magnetic field generators withdifferent pole tip configurations;

FIG. 18 is a cross-sectional view of a magnetic separator device havinga channel plate with two channels and two magnetic field generatorsoperated in parallel;

FIG. 19 is a cross-sectional view of a magnetic separator device havinga channel plate with two channels and an integrated magnetic fieldgenerator;

FIG. 20 is a cross-sectional view of a magnetic separator device havinga channel plate with three channels and an integrated magnetic fieldgenerator;

FIG. 21 is a cross-sectional view of a magnetic separator device havinga channel plate with two channels and two magnetic field generatorsoperated in parallel;

FIG. 22 is a cross-sectional view of a magnetic separator device havinga channel plate with two channels and an integrated magnetic fieldgenerator;

FIGS. 23A and 23B are cross-sectional views showing structure of achannel plate comprising two components;

FIG. 24 is a cross-sectional view showing a magnetic separator deviceutilizing a channel plate with a magnetic substrate;

FIGS. 25A and 25B are cross-sectional views showing structure of achannel plate comprising three components;

FIG. 26 is a cross-sectional view of a magnetic separator deviceutilizing a channel plate with a magnetic substrate;

FIG. 27 is a cross-sectional view of a magnetic separator deviceutilizing a channel plate with a magnetic cover plate;

FIG. 28 is a cross-sectional view of a magnetic separator deviceutilizing a magnetic top shield in combination with a magnetic fieldgenerator;

FIG. 29 is a cross-sectional view of a magnetic separator deviceutilizing another magnetic top shield in combination with a magneticfield generator;

FIG. 30 is a cross-sectional view of a magnetic separator deviceincluding a magnetic top shield and a magnetic field generator withstraight side poles;

FIG. 31 is a cross-sectional view of a magnetic separator deviceincluding a magnetic field generator with straight side poles in contactwith or in close proximity to a magnetic top shield;

FIG. 32 is a cross-sectional view of another magnetic separator deviceincluding a magnetic field generator with straight side poles in contactwith or in close proximity to a magnetic top shield;

FIG. 33A is a cross-sectional view showing accumulation of magneticallylabeled biological objects on the channel wall after a sortingoperation;

FIG. 33B is a cross-sectional view showing dissociation ordisintegration of magnetic conglomerates in the channel into individualbiological objects by using a motor to apply vibration force to thechannel plate;

FIG. 33C is a cross-sectional view showing dissociation ordisintegration of magnetic conglomerates in the channel into individualbiological objects by using one or more piezoelectric transducers toapply vibration force to the channel plate;

FIG. 34 is a cross-sectional view showing a channel plate and relevantdimensions;

FIG. 35 is a cross-sectional view of a magnetic separator device havinga conduit nestled in the gap formed between the pole tips of a magneticfield generator;

FIG. 36 is a cross-sectional view showing a press pushing the conduitagainst the gap formed between the pole tips of a magnetic fieldgenerator; and

FIG. 37 is a cross-sectional view showing another press pushing theconduit against the gap formed between the pole tips of a magnetic fieldgenerator.

For purposes of clarity and brevity, like elements and components willbear the same designations and numbering throughout the Figures, whichare not necessarily drawn to scale.

DETAILED DESCRIPTION

In the Summary above and in the Detailed Description, and the claimsbelow, and in the accompanying drawings, reference is made to particularfeatures (including method steps) of the invention. It is to beunderstood that the disclosure of the invention in this specificationincludes all possible combinations of such particular features. Forexample, where a particular feature is disclosed in the context of aparticular aspect or embodiment of the invention, or a particular claim,that feature can also be used, to the extent possible, in combinationwith and/or in the context of other particular aspects and embodimentsof the invention, and in the invention generally.

Where reference is made herein to a method comprising two or moredefined steps, the defined steps can be carried out in any order orsimultaneously, except where the context excludes that possibility, andthe method can include one or more other steps which are carried outbefore any of the defined steps, between two of the defined steps, orafter all the defined steps, except where the context excludes thatpossibility.

The term “at least” followed by a number is used herein to denote thestart of a range beginning with that number, which may be a range havingan upper limit or no upper limit, depending on the variable beingdefined. For example, “at least 1” means 1 or more than 1. The term “atmost” followed by a number is used herein to denote the end of a rangeending with that number, which may be a range having 1 or 0 as its lowerlimit, or a range having no lower limit, depending upon the variablebeing defined. For example, “at most 4” means 4 or less than 4, and “atmost 40%” means 40% or less than 40%. When, in this specification, arange is given as “a first number to a second number” or “a firstnumber-a second number,” this means a range whose lower limit is thefirst number and whose upper limit is the second number. For example,“25 to 100 nm” means a range whose lower limit is 25 nm and whose upperlimit is 100 nm.

The term “biological objects” may be used herein to include cells,bacteria, viruses, molecules, particles including RNA and DNA, cellcluster, bacteria cluster, molecule cluster, and particle cluster.

The term “biological sample” may be used herein to include blood, bodyfluid, tissue extracted from any part of the body, bone marrow, hair,nail, bone, tooth, liquid and solid from bodily discharge, or surfaceswab from any part of body. “Fluid sample,” or “sample fluid,” or“liquid sample,” or “sample solution” may include a biological sample inits original liquid form, biological objects being dissolved ordispersed in a buffer liquid, or a biological sample dissociated fromits original non-liquid form and dispersed in a buffer fluid. A bufferfluid is a liquid into which biological objects may be dissolved ordispersed without introducing contaminants or unwanted biologicalobjects. Biological objects and biological sample may be obtained fromhuman or animal. Biological objects may also be obtained from plants andenvironment including air, water, and soil. A fluid sample may containvarious types of magnetic or optical labels, or one or more chemicalreagents that may be added during various process steps.

The term “sample flow rate” or “flow rate” may be used herein torepresent the volume amount of a fluid sample flowing through a crosssection of a channel, or a conduit, or a fluidic part, or a fluidic pathin a unit time.

The term “relative fraction” may be used herein to represent the ratioof a given quantity of biological objects or particles to the totalquantity of all biological objects or particles present in a fluidsample.

In the art of cell sorting or enrichment, the target population ofbiological objects is referred to as the “specific” objects of interestand those biological objects that are isolated, but are not desired, aretermed “non-specific.” The term “purity” describes the concentration orrelative fraction of target or specific biological objects of interestand is quantified by the number of target biological objects divided bythe total number of biological objects expressed in percentage. The term“recovery ratio” describes the sorting efficiency of biological objectsand is quantified by the number of target biological objects recoveredafter sorting divided by the number of target biological objects presentin the initial sample expressed in percentage.

FIG. 7 is a cross-sectional view showing an embodiment of the presentinvention as applied to a magnetic separator device for separating orsorting biological objects. The magnetic device 150 includes a magneticfield generator 152, which comprises a soft magnetic center pole 154having a bottom end 156 and a tapered tip end 158; a first soft magneticside pole 160 and a second soft magnetic side pole 162 disposed onopposite sides of the soft magnetic center pole 154 and respectivelyhaving first and second bottom ends 164 and 166, the first and secondsoft magnetic side poles 160 and 162 respectively having first andsecond top ends 168 and 170 that are bent inward toward the softmagnetic center pole 154 with a first outward side 172 of the first topend 168 and a second outward side 174 of the second top end 170 beingsubstantially coplanar; and a magnetic flux source or a means forgenerating magnetic flux in the soft magnetic center pole 154 and thefirst and second soft magnetic side poles 160 and 162. The first andsecond soft magnetic side poles 160 and 162 may be substantiallyparallel to each other at or near their respective bottom ends 164 and166. The magnetic device 150 further includes a channel plate 176including a channel 178 embedded therein and having a substantially flatsurface 180 that is operable to be in contact with or in close proximityto (e.g., 1 mm or less) the first and second outward sides 172 and 174.The magnetic device 150 extends along a direction perpendicular to thecross section thereof.

The magnetic flux 182 is concentrated from the bottom end 156 to thetapered tip end 158 of the soft magnetic center pole 154 and is dividedbetween the first and second top ends 168, 170. The magnetic flux formsa first flux closure 182, 184 between the soft magnetic center pole 154and the first soft magnetic side pole 160 and a second flux closure 182,186 between the soft magnetic center pole 154 and the second softmagnetic side pole 162.

For the embodiment shown in FIG. 7 , the magnetic flux source or themeans for generating magnetic flux includes a soft magnetic bottomshield 188 disposed beneath the first and second bottom ends 164 and166, and a permanent magnet 190 disposed between the bottom end 156 ofthe soft magnetic center pole 154 and the soft magnetic bottom shield188. The magnetization direction 192 of the permanent magnet 190 may beoriented in a direction parallel to the soft magnetic center pole 154.The magnetization direction 192 may alternatively be oriented in adirection opposite to that shown in FIG. 7 .

With continuing reference to FIG. 7 , the tapered tip end 158, which isdisposed between the first and second top ends 168 and 170, may reach asurface that is coplanar with the first and second outward sides 172 and174. The tapered tip end 158 may be equally spaced from the first andsecond top ends 168 and 170. The soft magnetic center pole 154 may beattached or disposed in close proximity to (e.g., 1 mm or less) the Nsurface of the permanent magnet 190 at the bottom end 156, whichcollects magnetic flux 182 from the N surface of the permanent magnet190. The magnetic flux 182 may then be emitted from the tapered tip end158, which is much smaller than the bottom end 156, to produce a locallyhigh magnetic field around the tapered tip end 158 by concentrating themagnetic flux 182 conducted from the permanent magnet 190. Because ofthe tapered shape of the soft magnetic center pole 154 near its tip, theflux density at the tapered tip end 158 may be much higher than the fluxdensity at the bottom end 156.

The first and second bottom ends 164 and 166 of the first and secondsoft magnetic side poles 160 and 162 may be attached or disposed inclose proximity to (e.g., 1 mm or less) the top surface of the softmagnetic bottom shield 188. The top surface of the soft magnetic bottomshield 188 may also be attached or disposed in close proximity to (e.g.,1 mm or less) the S surface of the permanent magnet 190. Therefore, themagnetic flux 184, 186 generated from the S surface of the permanentmagnet 190 is conducted through the soft magnetic bottom shield 188 anddivided between the first and second soft magnetic side poles 160 and162. The first and second top ends 168 and 170 may have smaller crosssection area than the first and second bottom ends 164 and 166,respectively. The magnetic flux 184, 186 may be concentrated and emittedfrom the first and second top ends 168 and 170 and/or the first andsecond outward sides 172 and 174. The bending of the first and secondtop ends 168 and 170 toward the tapered tip end 158 allows the mainbodies of the first and second soft magnetic side poles 160 and 162 tobe disposed further apart from the main body of the soft magnetic centerpole 154, thereby reducing potential magnetic flux leakage andmaximizing the magnetic flux around the ends 158, 168 and 170. Since themagnetic flux 182 conducted by the soft magnetic center pole 154 hasopposite direction compared to the magnetic flux 184 and 186 conductedby the first and second soft magnetic side poles 160 and 162, a part ofthe magnetic flux 182 will flow into the first soft magnetic side pole160 through the space between the tapered tip end 158 and the first topend 168 and/or the first outward side 172, while another part of themagnetic flux 182 will flow into the second soft magnetic side pole 162through the space between the tapered tip end 158 and the second top end170 and/or the second outward side 174. Therefore, the flux generated bythe permanent magnet 190 forms a first flux closure 182, 184 thatcirculates between the soft magnetic center pole 154, the first softmagnetic side pole 160, and the soft magnetic bottom shield 188, and asecond flux closure 182, 186 that circulates between the soft magneticcenter pole 154, the second soft magnetic side pole 162, and the softmagnetic bottom shield 188. Since the magnetic flux 182 conducted in thesoft magnetic center pole 154 is divided between the first and secondsoft magnetic side poles 160 and 162, the tapered tip end 158 may havehigher flux density than the first and second top ends 168, 170 or thefirst and second outward sides 172, 174, as indicated by the closer fluxline spacing. High magnetic flux density around the tips 158, 168, and170 would result in high magnetic field and magnetic field gradient inthe vicinity around the tips 158, 168, and 170.

The soft magnetic center pole 154, the first and second soft magneticside poles 160 and 162, and the soft magnetic bottom shield 188 may eachbe made of a soft magnetic material or a material with relatively highmagnetic permeability that comprises any one of iron (Fe), cobalt (Co),nickel (Ni), or any combination thereof. In an embodiment, the poles154, 160, and 162 and shield 188 are made of permalloy, which is analloy comprising iron and nickel.

The center of the channel 178 in the channel plate 176 may besubstantially aligned to the tapered tip end 158. The width of thechannel 178 may be narrower than the gap between the first and secondtop ends 168, 170. The design of the poles 154, 160, and 162 and theplacement of the channel 178 in close proximity to the poles 154, 160,and 162 allow high magnetic field and high magnetic field gradient toexist inside the channel 178. During a sorting operation, a fluid samplecontaining nonmagnetic biological objects and biological objects labeledwith magnetic beads may flow through the channel 178 as shown in FIG. 8. The magnetically labeled biological objects 194 may condense oraccumulate to form one or more magnetic conglomerates or aggregates onthe channel walls, especially on the bottom wall where the magneticfield gradient may be particularly high owing to its proximity to thetapered tip end 158. The channel plate 176 may alternatively bepositioned in close proximity to (e.g., less than 1 mm) rather than incontact with the first and second outward sides 172, 174 during thesorting operation as shown in FIG. 9 . The channel plate 176 may bedetached or removed from the first and second outward sides 172 and 174to demagnetize the magnetic conglomerates after the sorting operation asshown in FIG. 10 . The channel plate 176 may be fabricated from anynonmagnetic material, such as but not limited to, silicon, glass, metal,ceramic, or any combination thereof.

The magnetic field generator 152 shown in FIG. 7 may utilize differentmagnetic flux sources or means for generating magnetic flux to attain ananalogous flux distribution in the three poles 154, 160, and 162. Forexample, FIG. 11 is a cross-sectional view of another magnetic device200 for separating or sorting magnetized biological objects fromnonmagnetic biological objects in a fluid sample. The magnetic device200 has a magnetic field generator 202 that is analogous to the magneticfield generator 152 except for the magnetic flux source or the means forgenerating the magnetic flux. Like the magnetic field generator 152, themagnetic field generator 202 also includes a soft magnetic center pole204 having a bottom end 206 and a tapered tip end 208; a first softmagnetic side pole 160 and a second soft magnetic side pole 162 disposedon opposite sides of the soft magnetic center pole 204 and respectivelyhaving first and second bottom ends 164 and 166, the first and secondsoft magnetic side poles 160 and 162 respectively having first andsecond top ends 168 and 170 that are bent inward toward the softmagnetic center pole 204 with a first outward side 172 of the first topend 168 and a second outward side 174 of the second top end 170 beingsubstantially coplanar; and a magnetic flux source or a means forgenerating magnetic flux in the soft magnetic center pole 204 and thefirst and second soft magnetic side poles 160 and 162. The first andsecond soft magnetic side poles 160 and 162 may be substantiallyparallel to each other at or near their respective bottom ends 164 and166. The magnetic device 200 further includes a channel plate 176 havinga channel 178 embedded therein and having a substantially flat surface180 that is operable to be in contact with or in close proximity to(e.g., 1 mm or less) the first and second outward sides 172 and 174. Themagnetic device 200 extends along a direction perpendicular to the crosssection thereof.

The magnetic flux source or the means for generating the magnetic fluxincludes a first permanent magnet 210 disposed between the first softmagnetic side pole 160 and the soft magnetic center pole 204 and asecond permanent magnet 212 disposed between the second soft magneticside pole 162 and the soft magnetic center pole 204. The first andsecond permanent magnets 210 and 212 have opposite magnetizationdirections 214 and 216 that are oriented substantially perpendicular tothe soft magnetic center pole 204. The N faces of the permanent magnets210 and 212 may be disposed adjacent to the soft magnetic center pole204 as shown in FIG. 11 . Alternatively, the S faces of the permanentmagnets 210 and 212 may be disposed adjacent to the soft magnetic centerpole 204 (not shown). Both configurations would generate magnetic fluxthat is concentrated from the bottom end 206 to the tapered tip end 208of the soft magnetic center pole 204 and is divided between the firstand second top ends 168, 170. The magnetic flux forms a first fluxclosure between the soft magnetic center pole 204 and the first softmagnetic side pole 160 and a second flux closure between the softmagnetic center pole 204 and the second soft magnetic side pole 162.

Further examples of the magnetic flux source or the means for generatingthe magnetic flux including three permanent magnets are shown in FIGS.12 and 13 , respectively. FIG. 12 is a cross-sectional view of amagnetic field generator 218 having the magnetic flux source or themeans for generating the magnetic flux that includes a soft magneticbottom shield 188, a first permanent magnet 220 disposed between a firstbottom end 164 of a first soft magnetic side pole 160 and the softmagnetic bottom shield 188, a second permanent magnet 222 disposedbetween a second bottom end 166 of a second soft magnetic side pole 162and the soft magnetic bottom shield 188, and a third permanent magnet224 disposed between a bottom end 206 of a soft magnetic center pole 204and the soft magnetic bottom shield 188. The magnetization direction thethird permanent magnet 224 may be substantially parallel to the softmagnetic center pole 204 and is substantially opposite to magnetizationdirections of the first and second permanent magnets 220, 224. Themagnetization directions of the three permanent magnets 220-224 mayalternatively be oriented in directions opposite to those shown in FIG.12 .

FIG. 13 is a cross-sectional view of a magnetic field generator 226having the magnetic flux source or the means for generating the magneticflux that includes the first permanent magnet 220 disposed beneath afirst bottom end 164 of a first soft magnetic side pole 160, a secondpermanent magnet 222 disposed beneath a second bottom end 166 of asecond soft magnetic side pole 162, and a third permanent magnet 224disposed beneath a bottom end 206 of a soft magnetic center pole 204.The magnetization direction of the third permanent magnet 224 may besubstantially parallel to the soft magnetic center pole 204 and issubstantially opposite to magnetization directions of the first andsecond permanent magnets 220, 222. The magnetization directions of thethree permanent magnets 220-224 may alternatively be oriented indirections opposite to those shown in FIG. 13 . The magnetic flux sourcefor the magnetic field generator 226 is analogous to that of themagnetic field generator 218 shown in FIG. 12 except for the lack of thesoft magnetic bottom shield 188.

Despite having different magnetic flux sources, each of the magneticfield generators 152, 202, 218, and 226 may generate magnetic flux inthe soft magnetic center pole 154 or 204 that is divided between thefirst and second soft magnetic side poles 160 and 162, thereby forming afirst flux closure between the soft magnetic center pole 154 or 204 andthe first soft magnetic side pole 160 and a second flux closure betweenthe soft magnetic center pole 154 or 204 and the second soft magneticside pole 162.

The magnetic field generators 152, 202, 218, and 226, as shown in FIGS.7-13 , may utilize different pole shapes to generate the magnetic fluxdistribution analogous to that shown in FIG. 7 . For example, FIG. 14 isa cross-sectional view showing a magnetic field generator 228 that isanalogous to the magnetic field generator 152 except for the shape ofthe first and second soft magnetic side poles 230 and 232, the tips ofwhich kink inward toward the soft magnetic center pole 154 rather thangradually curled inward.

FIGS. 15-17 further show other tip shapes that may be utilized with themagnetic field generators 152, 202, 218, and 226. Like the magneticfield generator 228, the magnetic field generators 234-238 have firstsoft magnetic side poles 240/242 and second soft magnetic side poles244/246 that kink inward near their top ends. For each of the magneticfield generators 234-238, the portion of the first soft magnetic sidepole 240/242 between the top end and the kink, which is horizontal andis perpendicular to the main body of the pole 240/242, may have aconstant width that is substantially narrower than the width at thecorresponding first bottom end 248/250. Similarly, the portion of thesecond soft magnetic side pole 244/246 between the top end and the kinkmay have a constant width that is substantially narrower than the widthat the corresponding second bottom end 252/254. Additionally, the topends 256, 258 of the first and second soft magnetic side poles 240 and244 of the magnetic field generator 234 shown in FIG. 15 may have ablunt shape. The top ends 260, 262 of the first and second soft magneticside poles 242 and 246 of the magnetic field generators 236 and 238shown in FIGS. 16 and 17 may have a chisel edge profile with the bevelside facing inward or an edge of the tapered tip end of the softmagnetic center pole 154/264. Furthermore, FIG. 16 shows the tapered tipend 266 of the soft magnetic center pole 264 may be blunt or flat and issubstantially coplanar with the first and second outward sides 268, 270of the first and second soft magnetic side poles 242 and 246. Any of thepole shapes and geometries shown in FIGS. 7 and 14-17 may be combinedwith any of the magnetic flux sources shown in FIGS. 7-14 to form amagnetic field generator that may generate the desired magneticflux/field distribution shown in FIGS. 7-11 and 14 .

Two or more of the magnetic field generators 152, 202, 218, 226, 228,and 236-238 or any combination thereof may operate in parallel togetherto increase the throughput. FIG. 18 shows a magnetic device 270including an array of two magnetic field generators 202 and a channelplate 272 including therein two channels 178 instead of two separateplates 176, each of which has one channel 178. The channel plate 272with two channels 178 is operable to be in contact with or in closeproximity to (e.g., 1 mm or less) to the first and second outward sides172 and 174. The center of each of the channels 178 of the channel plate272 may be substantially aligned to the respective tapered tip end 208of the soft magnetic center pole 204, thereby maximizing the magneticfield and field gradient in the channel 178.

The soft magnetic side poles of adjacent magnetic devices may also becombined or integrated to save space when multiple magnetic fieldgenerators are deployed. FIG. 19 shows an integrated magnetic fieldgenerator 274 including two magnetic field generators, each of which hasthe magnetic flux source of the magnetic field generator 202 and theside pole shape of the magnetic field generator 228. The two adjacentside poles, the right side-pole of the left device and the leftside-pole of the right device, may be combined to form a single pole 276with two top ends, with the left top end conducts flux from thegenerator of the left device and the right top end conducts flux fromthe generator of the right device. The channel plate 272 with twochannels 178 is operable to be in contact with or in close proximity to(e.g., 1 mm or less) to the outward sides 278-282 of the poles 230, 232,and 276 of the integrated magnetic field generator 274. The center ofeach the channels 178 of the channel plate 272 may be substantiallyaligned to the respective tapered tip end 208 of the soft magneticcenter pole 204, thereby maximizing the magnetic field and fieldgradient in the channel 178. The principle for integrating multiplemagnetic devices as described above may be applied to an array of threeor more magnetic field generators as shown in FIG. 20 .

FIG. 21 shows a magnetic device 288 including an array of two magneticfield generators 290 and a channel plate 272 including therein twochannels 178. The magnetic field generator 290 is similar to themagnetic field generator 202 shown in FIGS. 11 and 18 except that thetapered tip end 292 of its soft magnetic center pole 294 protrudes abovethe first and second outward sides 172, 174 of the first and second softmagnetic side poles 160 and 162. The channel plate 272 with two channels178 is operable to be in contact with or in close proximity to (e.g., 1mm or less) the tapered tip ends 292 of the soft magnetic center poles294. The center of each of the channels 178 of the channel plate 272 maybe substantially aligned to the respective tapered tip end 292 of thesoft magnetic center pole 294, thereby maximizing the magnetic field andfield gradient in the channel 178. The protruded soft magnetic centerpoles 294 shown in FIG. 21 may be combined with any of the side poleshape geometry shown in FIGS. 7 and 14-17 .

The soft magnetic side poles 162 and 160 of two adjacent magnetic fieldgenerators 290 may also be combined or integrated to save space whenmultiple magnetic field generators 290 are deployed. FIG. 22 shows anintegrated magnetic field generator 296 including two magnetic fieldgenerators, each of which has the magnetic flux source of the magneticfield generator 202, the side pole geometry of the magnetic fieldgenerator 274, and the center pole geometry of the magnetic fieldgenerator 290. The two adjacent side poles, the right side-pole of theleft device and the left side-pole of the right device, may be combinedto form a single pole 276 with two top ends, with the left top endconducts flux from the generator of the left device and the right topend conducts flux from the generator of the right device. The channelplate 272 with two channels 178 is operable to be in contact with or inclose proximity to (e.g., 1 mm or less) the tapered tip ends 292 of thesoft magnetic center poles 294. The center of each of the channels 178of the channel plate 272 may be substantially aligned to the respectivetapered tip end 292 of the soft magnetic center pole 294, therebymaximizing the magnetic field and field gradient in the channel 178.

FIGS. 23A and 23B are cross-sectional views of a channel plate 297,which extends along a direction substantially perpendicular to thefigure. The channel plate 297 may include a substrate 298 with a channel178 formed in the first of two planar surfaces 300 and 302 thereof and acover plate 304 attached or bonded to the first planar surface of thesubstrate 300 and covers the channel 178. An exterior surface 306 of thecover plate 304 of the channel plate 297 may face a magnetic fieldgenerator during operation. Alternatively, the second planar surface 302of the substrate 298 of the channel plate 297 may face the magneticfield generator. The channel 178 may be formed by etching into the firstplanar surface 300 of the substrate 298 and may have a rectangular,semicircular, semielliptical, triangular, or other cross section shapes.

To avoid the diversion of the magnetic field away from the channel 178,the component of the channel plate 297 that faces the magnetic fieldgenerator, either the substrate 298 or the cover plate 304, may comprisea nonmagnetic material, such as but not limited to glass, polymer,silicon, silicon carbide, a ceramic material, austenitic steel, or anonmagnetic metal. The component of the channel plate 297 that facesaway from the magnetic field generator, either the substrate 298 or thecover plate 304, may also comprise a nonmagnetic material as describedabove, such as but not limited to glass, polymer, silicon, siliconcarbide, a ceramic material, austenitic steel, or a nonmagnetic metal.Alternatively, the substrate 298 or the cover plate 306 that faces awayfrom the magnetic field generator may comprise a soft magnetic material,such as but not limited to nickel, iron, cobalt, permalloy, steel, orany combination thereof. Furthermore, the soft magnetic material mayhave a laminated structure that comprises layers of a soft magneticmaterial interleaved with layers of a nonmagnetic material in thethickness direction of the substrate 298 or the cover plate 304. Thewalls of the channel 178 in the channel plate 297 may be coated or linedwith a material that is inert to the sample fluid, such as but notlimited to glass, polymer, ceramic, or the likes. The structure andfabrication method for the channel plate 297 with single channel 178 mayalso be applied to other channel plates with multiple channels (e.g.,272, 286).

The use of a magnetic substrate 298 in the channel plate 297, whichconducts magnetic flux from the magnetic poles and functions as a partof the magnetic field generator 202, may further strengthen the magneticfield in the channel 178 of the magnetic device 307 as shown in FIG. 24. The magnetic flux distribution in the magnetic device 307 ischaracterized by two flux loops. The first loop is characterized by themagnetic flux flowing from the first permanent magnet 210 to the softmagnetic center pole 204, the magnetic substrate 298 of the channelplate 297, the first soft magnetic side pole 160, and back to the firstpermanent magnet 210. The second loop is characterized by the magneticflux flowing from the second permanent magnet 212 to the soft magneticcenter pole 204, the magnetic substrate 298 of the channel plate 297,the second soft magnetic side pole 162, and back to the second permanentmagnet 212. The magnetic flux will flow in opposite directions if themagnetization directions of the permanent magnets 210 and 212 arereversed.

FIGS. 25A and 25 show that a channel plate 308 may alternativelycomprise three components: a substrate 310 with a channel 178 formedthrough its thickness, a first cover plate 312 attached or bonded to afirst planar surface 314 of the substrate 310 and covers the channel178, and a second cover plate 316 attached or bonded to a second planarsurface 318 of the substrate 310 and covers the channel 178. The channel178 may be formed by etching after the substrate 310 is first bonded tothe first or second cover plate 312/316. An external surface 320 of thefirst cover plate 312 of the channel plate 308 may face a magnetic fieldgenerator.

To avoid the diversion of the magnetic field away from the channel 178,the first cover plate 312, which faces a magnetic field generator, maycomprise a nonmagnetic material, such as but not limited to glass,polymer, silicon, silicon carbide, a ceramic material, austenitic steel,or a nonmagnetic metal. The substrate 310 may comprise a nonmagneticmaterial as described above or a magnetic material, such as but notlimited to nickel, iron, cobalt, permalloy, steel, or any combinationthereof. The second cover plate 306 may comprise a nonmagnetic materialor a soft magnetic material as described above. Furthermore, the softmagnetic material may have a laminated structure that comprises layersof a soft magnetic material interleaved with layers of a nonmagneticmaterial along the thickness direction of the substrate 310 or thesecond cover plate 316. In an embodiment, only the substrate 310 is madeof a soft magnetic material. In another embodiment, only the secondcover plate 316 is made of a soft magnetic material. In still anotherembodiment, the substrate 310 and the second cover plate 316 are eachmade of a soft magnetic material. The walls of the channel 178 in thechannel plate 308 may be coated or lined with a material that is inertto the sample fluid, such as but not limited to glass, polymer, ceramic,or the likes. The structure and fabrication method for the channel plate308 with single channel 178 may also be applied to other channel plateswith multiple channels (e.g., 272, 286).

The use of a magnetic substrate 310 in the channel plate 308, whichconducts magnetic flux from the magnetic poles and functions as a partof a magnetic field generator, may further strengthen the magnetic fieldin the channel 178 of the magnetic device 320 as shown in FIG. 26 . Themagnetic flux distribution in the magnetic device 320 is characterizedby two flux loops. The first loop is characterized by the magnetic fluxflowing from the first permanent magnet 210 to the soft magnetic centerpole 204, the soft magnetic substrate 210 of the channel plate 308, thefirst soft magnetic side pole 160, and back to the first permanentmagnet 210. The second loop is characterized by the magnetic fluxflowing from the second permanent magnet 212 to the soft magnetic centerpole 204, the soft magnetic substrate 310 of the channel plate 308, thesecond soft magnetic side pole 162, and back to the second permanentmagnet 212. The magnetic flux will flow in opposite directions if themagnetization directions of the permanent magnets 210 and 212 arereversed.

FIG. 27 shows a magnetic device 322 comprising a magnetic fieldgenerator 324 and a channel plate 308 that includes a soft magneticsecond cover plate 316, a nonmagnetic substrate 310, and a nonmagneticfirst cover plate 312. The magnetic field generator 324 has the sidepoles 230 and 232 of the magnetic field generator 228 shown in FIG. 14and the magnetic flux source of the magnetic field generator 202 shownin FIG. 11 . The magnetic flux distribution in the magnetic device 322is characterized by four flux loops. The first loop is characterized bythe magnetic flux flowing from the first permanent magnet 210 to thesoft magnetic center pole 204, the soft magnetic second cover plate 316of the channel plate 308, the first soft magnetic side pole 230, andback to the first permanent magnet 210. The second loop is characterizedby the magnetic flux flowing from the first permanent magnet 210 to thesoft magnetic center pole 204, the first soft magnetic side pole 230,and back to the first permanent magnet 210. The third loop ischaracterized by the magnetic flux flowing from the second permanentmagnet 212 to the soft magnetic center pole 204, the soft magneticsecond cover plate 316 of the channel plate 308, the second softmagnetic side pole 232, and back to the second permanent magnet 212. Thefourth loop is characterized by the magnetic flux flowing from thesecond permanent magnet 212 to the soft magnetic center pole 204, thesecond soft magnetic side pole 232, and back to the second permanentmagnet 212. The magnetic flux concentrated from the bottom end 206 tothe tapered tip end 208 of the soft magnetic center pole 204 is dividedbetween the first and second top ends 324, 326 and the soft magneticsecond cover plate 316 of the channel plate 308. The magnetic flux inthe soft magnetic second cover plate 306 of the channel plate 308conducted from the tapered tip end 208 is further divided between thefirst and second soft magnetic side poles 230 and 232.

The four-loop flux distribution may be similarly generated by a magneticdevice 328 shown in FIG. 28 . The magnetic device 328 includes amagnetic flux generator 324, a soft magnetic top shield 330 in the formof a plate, and a nonmagnetic channel plate 176 interposed between themagnetic flux generator 324 and the soft magnetic top shield 330. Inthis embodiment, the flux conduction functionality of the magneticsecond cover plate 316 of the channel plate 308 shown in FIG. 27 isessentially replaced by the soft magnetic top shield 330. The softmagnetic top shield 330 may be detached or removed from the channelplate 176 to facilitate the removal of the channel plate 176 from themagnetic field generator 324 after a sorting operation.

The magnetic field generator 324 includes a soft magnetic center pole204 having a bottom end 206 and a tapered tip end 208; a first softmagnetic side pole 230 and a second soft magnetic side pole 232 disposedon opposite sides of the soft magnetic center pole 204 and respectivelyhaving first and second bottom ends 332 and 334, the first and secondsoft magnetic side poles 230 and 232 respectively having first andsecond top ends 324 and 326 that bend or kink inward toward the softmagnetic center pole 204 with a first outward side 336 of the first topend 324 and a second outward side 338 of the second top end 326 beingsubstantially coplanar; and a magnetic flux source or a means forgenerating magnetic flux in the soft magnetic center pole 204, the firstand second soft magnetic side poles 230 and 232, and the soft magnetictop shield 330. The first and second soft magnetic side poles 230 and232 may be substantially parallel to each other at or near theirrespective bottom ends 332 and 334. The magnetic device 328 furthercomprises a channel plate 176 including a channel 178 embedded thereinand having a first planar surface that is operable to be in contact withor in close proximity to (e.g., 1 mm or less) the first and secondoutward sides 336 and 338 and a second planar surface that is operableto be in contact with or in close proximity to the soft magnetic topshield 330. The magnetic device 328 of FIG. 28 extends along a directionperpendicular to the cross section thereof.

The magnetic flux source or the means for generating the magnetic fluxincludes a first permanent magnet 210 disposed between the first softmagnetic side pole 230 and the soft magnetic center pole 204 and asecond permanent magnet 212 disposed between the second soft magneticside pole 232 and the soft magnetic center pole 204. The first andsecond permanent magnets 210 and 212 have opposite magnetizationdirections that are oriented substantially perpendicular to the softmagnetic center pole 204. In addition to the magnetic field generator324 shown in FIG. 28 , the soft magnetic top shield 330 may be used incombination with other magnetic field generators with any of the poleshapes shown in FIGS. 7 and 14-17 and any of the magnetic flux sourcesshown in FIGS. 7-13 .

The soft magnetic top shield 330 shown in FIG. 28 may be modified tofurther increase the magnetic field strength in the channel 178. FIG. 29shows a magnetic device 340 that includes a magnetic field generator324, a soft magnetic top shield 342, and a channel plate 176 interposedbetween the magnetic field generator 324 and the soft magnetic topshield 342. The channel plate 176 has a first planar surface that isoperable to be in contact with or in close proximity to (e.g., 1 mm orless) the first and second outward sides 336 and 338 of the magneticfield generator 324 and a second planar surface that is operable to bein contact with or in close proximity to the soft magnetic top shield342. The soft magnetic top shield 342 includes a center contact region344 aligned to the channel 178 and the tapered tip end 208 of the softmagnetic center pole 204, a first side contact region 346 aligned to thefirst soft magnetic side pole 230, and a second side contact region 348aligned to the second soft magnetic side pole 232. The three contactregions 344-348 of the soft magnetic top shield 342 are delineated bytwo trenches therebetween. The center contact region 344 conductsmagnetic flux from/to the tapered tip end 208 of the soft magneticcenter pole 204 through the channel plate 176. The first side contactregion 346 conducts magnetic flux from/to the first outward side 336 ofthe first soft magnetic side pole 230 through the channel plate 176. Thesecond side contact region 348 conducts magnetic flux from/to the secondoutward side 338 of the second magnetic side pole 232 through thechannel plate 176. The soft magnetic top shield 342 may be detached orremoved from the channel plate 176 to facilitate the removal of thechannel plate 176 from the magnetic field generator 324 after thesorting operation.

The magnetic flux distribution in the magnetic devices 328, 340 of FIGS.28 and 29 may be characterized by four flux loops. The first loop ischaracterized by the magnetic flux conducted from the first permanentmagnet 210 to the soft magnetic center pole 204, the soft magnetic topshield 330/342, the first soft magnetic side pole 230, and back to thefirst permanent magnet 210. The second loop is characterized by themagnetic flux conducted from the first permanent magnet 210 to the softmagnetic center pole 204, the first soft magnetic side pole 230, andback to the first permanent magnet 210. The third loop is characterizedby the magnetic flux conducted from the second permanent magnet 212 tothe soft magnetic center pole 204, the soft magnetic top shield 330/342,the second soft magnetic side pole 232, and back to the second permanentmagnet 212. The fourth loop is characterized by the magnetic fluxflowing from the second permanent magnet 212 to the soft magnetic centerpole 204, the second soft magnetic side pole 232, and back to the secondpermanent magnet 212. The magnetic flux concentrated from the bottom end206 to the tapered tip end 208 of the soft magnetic center pole 204 isdivided between the first and second top ends 324, 326 and the softmagnetic top shield 330/342. The magnetic flux in the soft magnetic topshield 330/342 conducted from the tapered tip end 208 is further dividedbetween the first and second soft magnetic side poles 230 and 232.

The magnetic flux distribution shown in the magnetic device of FIG. 29may be modified by using a different magnetic field generator 352 shownin FIG. 30 . Unlike the other magnetic field generators which have bentor kinked soft magnetic side poles, the first and second soft magneticside poles 354 and 356 of the magnetic field generator 352 shown in FIG.30 are straight and may not form flux closures directly with the softmagnetic center pole 204. The first soft magnetic side pole 354 has afirst top end 358 and a first bottom end 360. The second soft magneticside pole 356 has a second top end 362 and a second bottom end 364. Thefirst and second soft magnetic side poles 354 and 356 may besubstantially parallel to each other. The channel plate 176 has a firstplanar surface that is operable to be in contact with or in closeproximity to (e.g., 1 mm or less) the first and second top ends 358 and362 and a second planar surface that is operable to be in contact withor in close proximity to the soft magnetic top shield 342. The softmagnetic top shield 342 may be detached or removed from the channelplate 176 to facilitate the removal of the channel plate 176 from themagnetic field generator 352 after the sorting operation.

The tapered tip end 208 of the soft magnetic center pole 204 conductsmagnetic flux from/to the center contact region 344 of the soft magnetictop shield 342 through the channel plate 176. The first top end 358 ofthe first soft magnetic side pole 354 conducts magnetic flux from/to thefirst side contact region 346 of the soft magnetic top shield 342through the channel plate 176. The second top end 362 of the second softmagnetic side pole 356 conducts magnetic flux from/to the second sidecontact region 348 of the soft magnetic top shield 342 through thechannel plate 176. The magnetic flux distribution in the magnetic device350 of FIG. 22 may be characterized by two flux loops. The first loop ischaracterized by the magnetic flux conducted from the first permanentmagnet 210 to the soft magnetic center pole 204, the soft magnetic topshield 342, the first soft magnetic side pole 354, and back to the firstpermanent magnet 210. The second loop is characterized by the magneticflux conducted from the second permanent magnet 212 to the soft magneticcenter pole 204, the soft magnetic top shield 342, the second softmagnetic side pole 356, and back to the second permanent magnet 212.

The potential flux leakage between the soft magnetic top shield 342 andthe soft magnetic side poles 354 and 356 may be minimized or eliminatedby reducing the width of the channel plate 176 and bringing the firstand second top ends 358 and 362 to be in contact with or in closeproximity to (e.g., 2 mm or less) the first and second side contactregions 346 and 348, respectively. FIG. 31 shows such a magnetic device366, wherein the magnetic field generator 368 includes a first top end370 of a first soft magnetic side pole 372 and a second top end 374 of asecond soft magnetic side pole 376 in contact with or in close proximityto the first and second side contact regions 346 and 348, respectively.The channel plate 378 has first and second planar surfaces that areoperable to be in contact with or in close proximity to (e.g., 1 mm orless) the tapered tip end 208 of the soft magnetic center pole 204 andthe center contact region 344 of the soft magnetic top shield 342,respectively. The channel plate 378 is surrounded by the soft magnetictop shield 342 and the magnetic field generator 368. The soft magnetictop shield 342 may be detached or removed from the channel plate 378 andthe magnetic field generator 368 to facilitate the removal of thechannel plate 378 from the magnetic field generator 368 after thesorting operation. Providing a gap between the first and second top ends370 and 374 of the magnetic field generator 368 and the first and secondside contact regions 346 and 348 of the soft magnetic top shield 342would facilitate the subsequent removal of the soft magnetic top shield342 after a sorting operation.

FIG. 32 shows another magnetic device 380 that may reduce potential fluxleakage between a soft magnetic top shield 382 and the magnetic fieldgenerator 384 by bringing the first and second side contact regions 386and 388 to be in contact with or in close proximity to (e.g., 2 mm orless) the first and second top ends 358 and 362 of the first and secondsoft magnetic side poles 354 and 356, respectively. Unlike the softmagnetic top shield 342, whose contact regions 344-348 are essentiallycoplanar, the soft magnetic top shield 382 shown in FIG. 32 has thefirst and second side contact regions 386 and 388 that are not coplanarwith the center contact region 344.

After flowing a sample fluid containing magnetically labeled biologicalobjects 194 through the channel 178 positioned in close proximity to amagnetic field generator, the magnetically labeled biological objects194 may condense or accumulate to form one or more magneticconglomerates or aggregates on the walls of the channel 178 of thechannel plate 176/272/286/297/308/378, as shown in FIG. 33A. The channelplate 176/272/286/297/308/378, which includes a first planar surface 390that is facing the magnetic field generator and a second planar surface392, may then be removed from the magnetic field generator todemagnetize the magnetic conglomerates.

The dissociation or disintegration of the magnetic conglomerates in thechannel 178 into individual biological objects 194 may be facilitated bya mechanical means for applying vibration to the channel plate176/272/286/297/308/378. FIG. 33B shows that a motor 394 that producesvibration may be reversibly coupled to the channel plate176/272/286/297/308/378 and break up the magnetic conglomerates intoindividual biological objects 194. Another approach for applyingvibration is to use a channel plate 176/272/286/297/308/378 with one ormore piezoelectric transducers 396 attached to the first and/or secondplanar surface 390, 392 of the channel plate 176/272/286/297/308/378 asshown in FIG. 33C. The one or more piezoelectric transducers 396 may bepermanently attached or bonded to the channel plate176/272/286/297/308/378, becoming an integral part of the channel plate176/272/286/297/308/378. Alternatively, the one or more piezoelectrictransducers 396 may be reversibly attached to the channel plate176/272/286/297/308/378 after it is removed from the magnetic fieldgenerator.

When one or more piezoelectric transducers 396 are used as themechanical means for applying vibration, each of the width (w) andheight (h) of the channel 178, as shown in FIG. 34 , may be an integermultiple of one-half wavelength of the acoustic wave in the samplefluid. Moreover, each of the channel plate thickness (h₁), heightbetween the second planar surface 392 and the channel top wall (h₂),height between the first planar surface 390, which faces a magneticfield generator during operation, and the channel top wall (h₃), heightbetween the second planar surface 392 and the channel bottom wall (h₄),and height between the first planar surface 390 and the channel bottomwall (h₅) may be an integer multiple of one-half wavelength of theacoustic wave traveling in the solid material(s) of the channel plate176/272/286/297/308/378 itself.

The use of a mechanical means for applying vibration to the channelplate 176/272/286/297/308/378 to dissociate the magnetic conglomeratesin the channel 178 into individual biological objects 194 may beapplicable to a channel plate made of a single material or a channelplate composed of different materials as illustrated in FIGS. 23A/B and25A/B. Moreover, the mechanical means for applying vibration to thechannel plate 176/272/286/297/308/378 to dissociate the magneticconglomerates as discussed above may be used after the sorting operationby any of the magnetic field generators disclosed herein (e.g., 152,202, 218, 226, 228, 234-238, 274, 284, 290, 296, 324, 352, 368, 384).

FIG. 35 is a cross-sectional view showing a magnetic device 398 thatincludes a magnetic field generator 400 and a conduit 402 for flowing asample fluid for sorting instead of a channel plate. The magnetic fieldgenerator 400 includes a soft magnetic center pole 204 having a bottomend 206 and a tapered tip end 208; a first soft magnetic side pole 404and a second soft magnetic side pole 406 disposed on opposite sides ofthe soft magnetic center pole 204 and respectively having first andsecond bottom ends 408 and 410, the first and second soft magnetic sidepoles 404 and 406 respectively having first and second top ends 412 and414 that bend or kink inward toward the soft magnetic center pole 204 toform a first outward side 416 of the first top end 412 and a secondoutward side 418 of the second top end 414; and a magnetic flux sourceor a means for generating magnetic flux in the soft magnetic center pole204 and the first and second soft magnetic side poles 404 and 406. Theportion of the first soft magnetic side pole 404 between the first topend 412 and the kink, which may be horizontal and perpendicular to themain body of the pole 404, may have a constant width that issubstantially narrower than the width at the first bottom end 408.Similarly, the portion of the second soft magnetic side pole 406 betweenthe second top end 414 and the kink, which may be horizontal andperpendicular to the main body of the pole 406, may have a constantwidth that is substantially narrower than the width at the second bottomend 410. The first and second soft magnetic side poles 404 and 406 maybe substantially parallel to each other at or near their respectivebottom ends 408 and 410.

The first and second top ends 412 and 414 may each have a chisel edgeprofile with the bevel side facing upward or outward away from the softmagnetic center pole. The tapered tip end 208 may be positioned belowthe first and second outward sides 416, 418 or the first and second topends 412 and 414. The conduit 402 may be nestled in the gap formedbetween the tapered tip end 208 and the bevels of the first and secondtop ends 412 and 414.

The magnetic flux source or the means for generating the magnetic fluxincludes a first permanent magnet 210 disposed between the first softmagnetic side pole 404 and the soft magnetic center pole 204 and asecond permanent magnet 212 disposed between the second soft magneticside pole 406 and the soft magnetic center pole 204. The first andsecond permanent magnets 210 and 212 have opposite magnetizationdirections that may be oriented substantially perpendicular to the softmagnetic center pole 204. The N faces of the permanent magnets 210 and212 may be disposed adjacent to the soft magnetic center pole 204 asshown in FIG. 35 . Alternatively, the S faces of the permanent magnets210 and 212 may be disposed adjacent to the soft magnetic center pole204 (not shown). Both configurations would generate magnetic flux thatis concentrated from the bottom end 206 to the tapered tip end 208 ofthe soft magnetic center pole 204 and is divided between the first andsecond top ends 412, 414. The magnetic flux forms a first flux closurebetween the soft magnetic center pole 204 and the first soft magneticside pole 404 and a second flux closure between the soft magnetic centerpole 204 and the second soft magnetic side pole 406. The magnetic fieldgenerator 400 may alternatively utilize other magnetic flux sources,such as those shown in FIGS. 7-13 .

The conduit 402 may be made of a flexible or pliable material, such asbut not limited to rubber, plastic, or other polymeric materials. Theconduit 402 may be operable to be pressed and deformed against the bevelsurfaces of the first and second top ends 412, 414 and/or the taperedtip end 208 by a press 420 as shown in the magnetic device 422 of FIG.36 , thereby allowing the sample fluid to flow in closer proximity tothe first and second top ends 412, 414 and the tapered tip end 208 toexperience higher magnetic field gradient. The press 420 may be made ofa soft magnetic material or a material with relatively high magneticpermeability that comprises any one of iron (Fe), cobalt (Co), nickel(Ni), or any combination thereof. The soft magnetic press 420 mayfunction like the soft magnetic top shields 330 and 342 shown in FIGS.28 and 29 to generate the magnetic flux distribution characterized byfour flux loops. The first loop is characterized by the magnetic fluxflowing from the first permanent magnet 210 to the soft magnetic centerpole 204, the soft magnetic press 420, the first soft magnetic side pole404, and back to the first permanent magnet 210. The second loop ischaracterized by the magnetic flux flowing from the first permanentmagnet 210 to the soft magnetic center pole 204, the first soft magneticside pole 404, and back to the first permanent magnet 210. The thirdloop is characterized by the magnetic flux flowing from the secondpermanent magnet 212 to the soft magnetic center pole 204, the softmagnetic press 420, the second soft magnetic side pole 406, and back tothe second permanent magnet 212. The fourth loop is characterized by themagnetic flux flowing from the second permanent magnet 212 to the softmagnetic center pole 204, the second soft magnetic side pole 406, andback to the second permanent magnet 212. The magnetic flux concentratedfrom the bottom end 206 to the tapered tip end 208 of the soft magneticcenter pole 204 is divided between the first and second top ends 412,414 and the soft magnetic press 420. The magnetic flux in the softmagnetic press 420 conducted from the tapered tip end 208 is furtherdivided between the first and second soft magnetic side poles 404 and406.

The soft magnetic press 420 shown in FIG. 36 may have other shapes. Forexample, FIG. 37 shows another magnetic device 424 with a soft magneticpress 426 that is operable to press the conduit 402 against the bevelsurfaces of the first and second top ends 412, 414 and/or the taperedtip end 208. The soft magnetic press 426 has a triangular shape that maybe substantially conformal to the gap formed between the tapered tip end208 and the bevels of the first and second top ends 412 and 414. Thesoft magnetic press 426 may also conduct the magnetic flux with thefirst and second soft magnetic side poles 404 and 406 more efficiently.

What is claimed is:
 1. A magnetic device comprising: a soft magnetic center pole having a bottom end and a tapered tip end; first and second soft magnetic side poles disposed on opposite sides of the soft magnetic center pole and respectively having first and second bottom ends, the first and second soft magnetic side poles respectively having first and second top ends that bend inward toward the soft magnetic center pole with a first outward side of the first top end and a second outward side of the second top end being substantially coplanar; a magnetic flux source generating magnetic flux in the soft magnetic center pole and the first and second soft magnetic side poles; and a channel plate having a channel embedded therein and a first planar surface that is operable to be in contact with or in close proximity to the first and second outward sides.
 2. The magnetic device of claim 1, wherein the tapered tip end and the first and second outward sides are substantially coplanar.
 3. The magnetic device of claim 1 further comprising one or more piezoelectric transducers attached to the channel plate.
 4. The magnetic device of claim 1, wherein the magnetic flux forms a first flux closure between the soft magnetic center pole and the first soft magnetic side pole and a second flux closure between the soft magnetic center pole and the second soft magnetic side pole.
 5. The magnetic device of claim 1, wherein the magnetic flux source includes a soft magnetic bottom shield and a permanent magnet disposed between the soft magnetic bottom shield and the bottom end of the soft magnetic center pole, wherein the first and second bottom ends are disposed above the soft magnetic shield.
 6. The magnetic device of claim 1, wherein the magnetic flux source includes a soft magnetic bottom shield, a first permanent magnet disposed between the first bottom end and the soft magnetic bottom shield, a second permanent magnet disposed between the second bottom end and the soft magnetic bottom shield, and a third permanent magnet disposed between the bottom end of the soft magnetic center pole and the soft magnetic bottom shield, wherein a magnetization direction of the third permanent magnet is opposite to magnetization directions of the first and second permanent magnets.
 7. The magnetic device of claim 1, wherein the magnetic flux source includes a first permanent magnet disposed beneath the first bottom end, a second permanent magnet disposed beneath the second bottom end, and a third permanent magnet disposed beneath the bottom end of the soft magnetic center pole, wherein a magnetization direction of the third permanent magnet is opposite to magnetization directions of the first and second permanent magnets.
 8. The magnetic device of claim 1, wherein the magnetic flux source includes a first permanent magnet disposed between the first soft magnetic side pole and the soft magnetic center pole and a second permanent magnet disposed between the second soft magnetic side pole and the soft magnetic center pole, wherein the first and second permanent magnets have opposite magnetization directions.
 9. The magnetic device of claim 1, wherein the tapered tip end has a substantially higher magnetic flux density than the first and second top ends
 10. The magnetic device of claim 1, wherein the channel plate is made of a nonmagnetic material.
 11. The magnetic device of claim 1, wherein a portion of the channel plate is made of a magnetic material.
 12. The magnetic device of claim 11, wherein the magnetic flux is concentrated from the bottom end to the tapered tip end of the soft magnetic center pole and is divided between the magnetic portion of the channel plate and the first and second top ends.
 13. The magnetic device of claim 1 further comprising a soft magnetic top shield operable to be in contact with or in close proximity to a second planar surface of the channel plate, wherein the magnetic flux is concentrated from the bottom end to the tapered tip end of the soft magnetic center pole and is divided between the soft magnetic top shield and the first and second top ends.
 14. A magnetic device comprising: a soft magnetic center pole having a bottom end and a tapered tip end; first and second soft magnetic side poles disposed on opposite sides of the soft magnetic center pole and respectively having first and second bottom ends, the first and second soft magnetic side poles respectively having first and second top ends that are substantially coplanar; a channel plate including a channel embedded therein and a first planar surface operable to be in contact with or in close proximity to the tapered tip end; a soft magnetic top shield operable to be in contact with or in close proximity to a second planar surface of the channel plate; and a magnetic flux source generating magnetic flux in the soft magnetic center pole, the first and second soft magnetic side poles, and the soft magnetic top shield.
 15. The magnetic device of claim 14, wherein the first planar surface of the channel plate is operable to be in contact with or in close proximity to the first and second top ends.
 16. The magnetic device of claim 14, wherein the soft magnetic top shield is operable to be in contact with or in close proximity to the first and second top ends.
 17. The magnetic device of claim 14 further comprising one or more piezoelectric transducers attached to the channel plate.
 18. The magnetic device of claim 14, wherein the magnetic flux source includes a soft magnetic bottom shield and a permanent magnet disposed between the soft magnetic bottom shield and the bottom end of the soft magnetic center pole, wherein the first and second bottom ends are disposed above the soft magnetic shield.
 19. The magnetic device of claim 14, wherein the magnetic flux source includes a soft magnetic bottom shield, a first permanent magnet disposed between the first bottom end and the soft magnetic bottom shield, a second permanent magnet disposed between the second bottom end and the soft magnetic bottom shield, and a third permanent magnet disposed between the bottom end of the soft magnetic center pole and the soft magnetic bottom shield, wherein a magnetization direction of the third permanent magnet is opposite to magnetization directions of the first and second permanent magnets.
 20. The magnetic device of claim 14, wherein the magnetic flux source includes a first permanent magnet disposed beneath the first bottom end, a second permanent magnet disposed beneath the second bottom end, and a third permanent magnet disposed beneath the bottom end of the soft magnetic center pole, wherein a magnetization direction of the third permanent magnet is opposite to magnetization directions of the first and second permanent magnets.
 21. The magnetic device of claim 14, wherein the magnetic flux source includes a first permanent magnet disposed between the first soft magnetic side pole and the soft magnetic center pole and a second permanent magnet disposed between the second soft magnetic side pole and the soft magnetic center pole, wherein the first and second permanent magnets have opposite magnetization directions.
 22. A magnetic device comprising: a soft magnetic center pole having a bottom end and a tapered tip end; first and second soft magnetic side poles disposed on opposite sides of the soft magnetic center pole, the first soft magnetic side pole having a first bottom end and a first top end, the second soft magnetic side pole having a second bottom end and a second top end, the first and second top ends bending inward toward the soft magnetic center pole and each having a chisel edge profile with a bevel side facing outward away from the soft magnetic center pole; a magnetic flux source generating magnetic flux in the soft magnetic center pole and the first and second soft magnetic side poles; a flexible conduit nestled in a gap formed between the tapered tip end and the bevel sides of the first and second top ends; and a soft magnetic press operable to push and deform the flexible conduit nestled in the gap.
 23. The magnetic device of claim 22, wherein the magnetic flux source includes a soft magnetic bottom shield and a permanent magnet disposed between the soft magnetic bottom shield and the bottom end of the soft magnetic center pole, wherein the first and second bottom ends are disposed above the soft magnetic shield.
 24. The magnetic device of claim 22, wherein the magnetic flux source includes a soft magnetic bottom shield, a first permanent magnet disposed between the first bottom end and the soft magnetic bottom shield, a second permanent magnet disposed between the second bottom end and the soft magnetic bottom shield, and a third permanent magnet disposed between the bottom end of the soft magnetic center pole and the soft magnetic bottom shield, wherein a magnetization direction of the third permanent magnet is opposite to magnetization directions of the first and second permanent magnets.
 25. The magnetic device of claim 22, wherein the magnetic flux source includes a first permanent magnet disposed beneath the first bottom end, a second permanent magnet disposed beneath the second bottom end, and a third permanent magnet disposed beneath the bottom end of the soft magnetic center pole, wherein a magnetization direction of the third permanent magnet is opposite to magnetization directions of the first and second permanent magnets.
 26. The magnetic device of claim 22, wherein the magnetic flux source includes a first permanent magnet disposed between the first soft magnetic side pole and the soft magnetic center pole and a second permanent magnet disposed between the second soft magnetic side pole and the soft magnetic center pole, wherein the first and second permanent magnets have opposite magnetization directions. 